Saudi Journal of Ophthalmology (2013) 27, 241—246

Original Article

Sequential, non-arteritic anterior ischemic optic neuropathyin patients taking sildenafil: a report of ten cases

Peer review under responsibilityof Saudi Ophthalmological Society,King Saud University Production and hosting by Elsevier

Access this article onlinwww.saudiophthaljournwww.sciencedirect.com

Received 23 January 2013; received in revised form 8 July 2013; accepted 16 July 2013; available online 22 July 2013.

Division of Neuro-Ophthalmology, King Khaled Eye Specialist Hospital, Saudi Arabia

⇑ Corresponding author. Address: King Khaled Eye Specialist Hospital, Division of Neuro-ophthalmology, P.O. Box 7191, Riyadh 11462, SaudiTel.: +966 1 482 1234.e-mail addresses: algarui@yahoo.com, agalvez@kkesh.med.sa (A. Galvez-Ruiz).

Alberto Galvez-Ruiz, MD, PhD ⇑; Nawal Arishi, MD

Abstract

Aim/purpose: To present a summary of 10 cases of non-arteritic anterior ischemic optic neuropathy (NAION) in patients whoreceived phosphodiesterase type 5 (PDE-5) inhibitors.Methods: A case series of 10 patients who, after regular intake of Sildenafil, presented with a first episode of NAION in one eye.NAION was diagnosed based on the following criteria: acute, painless, unilateral loss of vision, fundus features consistent withNAION and exclusion of other possible causes.Results: Despite the initial adverse event (first episode of NAION), all of these patients continued to use the medication and devel-oped a second episode of NAION in the contralateral eye. Only one of the 10 patients presented with bilateral simultaneousNAION.Conclusion: This largest case series published to date, reinforces the general consensus that PDE-5 inhibitors are contraindicatedin patients with a history of unilateral NAION.

Keywords: Non-arteritic anterior ischemic optic neuropathy, Sildenafil, Phosphodiesterase type 5 inhibitors

� 2013 Production and hosting by Elsevier B.V. on behalf of Saudi Ophthalmological Society, King Saud University.http://dx.doi.org/10.1016/j.sjopt.2013.07.010

Introduction

There are more than 35 million users of Sildenafil (Viagra;Pfizer) worldwide since its introduction in 1998.1 Over timeother drugs belonging to the phosphodiesterase type 5inhibitors (PDE-5) have been introduced, including Tadalafil(Cialis; Eli Lilly) and Vardenafil (Levitra; Bayer) (see Fig. 1).

Oral intake of these PDE-5 inhibitors has been associated,albeit rarely, in cases of non-arteritic anterior ischemic opticneuropathy (NAION) in patients. However, it was unclearwhether these cases of NAION are secondary to PDE-5 inhib-itor intake, to the concomitant existence of cardiovascularrisk factors or a combination of factors.2

We present a series of 10 patients who, after a sustainedintake of Sildenafil, presented with their first episode of

NAION in one eye. Despite this adverse event, all of the pa-tients continued to use Sildenafil and later suffered a secondepisode of NAION in the contralateral eye. To the best of ourknowledge, this is the largest series to date of sequentialNAION in patients who received Sildenafil.

Methods and materials

A retrospective review was performed on 10 male pa-tients with a mean age of 50.7 years (range, 38 years and70 years) who were regularly ingesting Sildenafil. All of thepatients had cardiovascular risk factors, with diabetes beingthe most frequent risk factor. Data gathering with respect tothe exact dose of Sildenafil and the time elapsed betweenSildenafil intake and the manifestation of visual symptoms

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Arabia.

Figure 1. Fundoscopy of 10 patients from the clinical series showing the appearance of the optic nerve OU after episodes of non-arteritic, ischemic opticneuropathy. A. OD. B. OS.

242 A. Galvez-Ruiz, N. Arishi

were difficult in the majority of these patients. This difficultyis due in part to the scarce medical resources and the lackof importance attributed to medical treatment in the localpopulation in the remote regions of the country (where thisstudy was performed). However, all of the patients sharedthe characteristic of regular use of this Sildenafil (>2–3 timesper week) during the weeks and months prior to the onsetof ocular ischemia. The following criteria were required forthe diagnosis of NAION: acute, painless, unilateral loss of vi-sion, presence of fundus features compatible with NAIONsuch as optic disk edema with splinter hemorrhages in theacute setting with contralateral disk-at-risk and exclusionof other possible causes through Erythrocyte SedimentationRate (ESR), C-reactive protein (CRP), Anti-nuclear Ab (ANA),Anti-DNA, Treponema pallidum hemagglutination assay(TPHA), Rapid Plasma Reagin (RPR) and cranial and orbitalmagnetic resonance imaging (MRI) within normal limits (aswarranted).

This study was registered with the institutional reviewboard and was approved by the ethics committee of the insti-tution (King Khaled Eye Specialist Hospital).

Results

Case reports

Table 1 summarizes the patient data including demo-graphics, systemic and ophthalmic features, the interval be-tween the two episodes of NAION and Sildenafil dosage.

Discussion

We present a series of 10 patients who used Sildenafil fora prolonged period of time. All of these patients shared a

Table 1. Summarized information of the 10 patients showing age, gender, cardiovascular risks, first and second episode of NAION with fundoscopy and visual field if available, period of time between twoattacks and Sildenafil doses.

Age Cardiovascularrisk factors

First episodeNAION VA

Fundoscopy GVF First episode SecondepisodeNAIONVA

Fundoscopy GVF Second episode Period oftimebetweenepisodes

Sildenafildoses

Patient1

52 yearsmale

DM OD OD optic diskedema with peri-papillary splinterhemorrhages(Fig. 1. 1A)

Non available OS VA20/2020/40

OD: superior sectoralpallor OS: Optic diskedema with peri-papillary splinterhemorrhages (Fig. 1. 1B)

Absolute inferiornasal defect OU(Fig. 2. 2A–B)

1 month 100 mgroutinely (>2–3times permonth) for thepast year

Patient2

50 yearsmale

DM Ischemicheart disease

OS Non available Non available OD VA20/30020/100

Temporal papillary pallorOU (Fig. 1. 2A–B)

Absolute inferiornasal defect OU witha cecocentralscotoma OS (Fig. 2.2A–B)

6 months Routinely usedSildenafil forover a year

Patient3

52 yearsmale

DM OS Non available Non available OD VA20/2520/30

Superior sectoral pallorOU (Fig. 1. 3A-B)

HVF OD: inferioraltitudinal defectOS: Inferior nasalsector defect (Fig. 2.3A–B)

Severalmonths

He had usedSildenafilregularly forapproximatelytwo years (2–3times perweek)

Patient4

41 yearsmale

DM OS Non available Non available OD VA20/10020/30

Optic disk-at-risk wasobserved in the fundusof the eye with temporalpallor OU (Fig. 1. 4A–B)

OD: Superiorarcuate defect withinferior constrictionOS: inferiortemporal sector(Fig. 2. 4A–B)

Severalmonths

He had beentakingSildenafilregularly (>2–3times perweek)

Patient5

45 yearsmale

DM OS Non available Non available OD VA20/8020/30

Superior altitudinalpallor OU, with a smallpapillary excavation(disk-at-risk) (Fig. 1. 5A–B)

OU: inferioraltitudinal defect,although it was morepronounced OD(Fig. 2. 5A-B)

Unknown Patient hadtakenSildenafilregularly (>2–3times perweek) for6 months

Patient6

38 yearsmale

DMdyslipidemia

SimultaneousOU VA 20/3020/40

OD: superioraltitudinal pallorOS: temporalpallor (Fig. 1. 6A-B)

HVF: OD superiorsector defect withsuperior paracentralscotoma OS: inferioraltitudinal defect anda superior arcuatedefect (Fig. 2. 6A-B)

– – – Simultaneous Just before theevent, thepatient statedhaving takingSildenafil daily

Patient7

56 yearsmale

HypertensionHypercholes-terolemia

OD Non available No available OS VAHandmotionFingercount

Global pallor of the opticdisk, bilaterally, withoutexcavation (Fig. 1. 7A–B)

OD residual centraland temporal isletOS isopterconcentric reductionwith a nasal inferiordefect (Fig. 2. 7A–B)

3 weeks He had beentakingSildenafilregularly (>2–3times perweek) for 6–8 months prior

Patient8

51 yearsmale

DMdyslipidemia

OD OD: disk edemawith peri-papillary splinterhemorrhages OS:normal coloration

Non available OS VA20/2520/40

OD: temporal pallor OSoptic disk edema withperi-papillary splinterhemorrhages withpredominance in the

OD global sensibilitydecrease OS: aninferior nasal defect(Fig. 2. 8A–B)

Few months Sildenafilintake in thedays prior tothe vision lossOU

(continued on next page)

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244 A. Galvez-Ruiz, N. Arishi

common characteristic: regular intake of Sildenafil despite anepisode of NAION.

There is no general consensus regarding the possiblecause-and-effect relationship between the use of PDE-5medications and the onset of NAION. Some investigatorssuch as Gorkin et al.2 are reluctant to admit this relationshipbetween Viagra and NAION. However, others, such as Hay-reh3 suggest that Viagra and other PDE-5 inhibitors canclearly result in the development of NAION. Until 2011, thispossible relationship had been reported in 49 patients,mainly through case reports with varying levels of evidence.4

McGwin et al.[5] published one of the most importantstudies to clarify this possible relationship. McGwin et al.5

conducted a retrospective, matched, case-control study inwhich 38 male patients with a diagnosis of NAION and 38controls without NAION were included. Their5 results indi-cated a positive association between the intake of Viagraand/or Cialis and the risk of developing NAION (the odds ra-tio suggested an approximate increase of 75–80%). However,this association was not statistically significant. Sobel et al.6

questioned the validity of McGwin et al’s5 study by indicatingnumerous biases.

Studies similar to Gorkin et al’s2 propose that cases ofNAION in patients on PDE-5 are purely related due tochance. These authors2 argue that individuals who suffer fromerectile dysfunction and use PDE-5 medications have cardio-vascular risk factors with a greater frequency including diabe-tes, hypertension, dyslipidemia and tobacco use. Given thatthese cardiovascular risk factors increase the risk of develop-ing NAION, it is not surprising to find a greater frequency ofspontaneous NAION in individuals with erectile dysfunction.2

Gorkin et al.,2 analyzed data from the Global Clinical Trialsand the European Observational Studies and estimated theincidence of NAION after exposure to Sildenafil to be 2.8cases per 100,000 patients per year. Gorkin et al.2 comparedthis incidence to two studies of the incidence of NAION inthe general population.7,8 Using these comparisons, Gorkinet al.2 concluded that the incidence of NAION cases in pa-tients who take Sildenafil is similar to that of the general pop-ulation, ruling out a possible causal association or increasedoccurrence of NAION related to PDE-5. The validity of Gor-kin et al’s. study was questioned by others3 as Dr. Gorkinwas working for Pfizer, the manufacturer of Viagra, indicatinga serious conflict of interest.

A key component to the relationship between NAION andPDE-5 is establishing the mechanism of action of the medica-tion through which this complication occurs. Several studieshave hypothesized that PDE-5 produce an alteration or neg-ative influence in the auto-regulation of blood flow of the op-tic nerve.4,5,9

In light of these studies, it is difficult to establish a cause-effect relationship between PDE-5 use and the developmentof NAION.10 However Hayreh3 proposes that ‘‘all the avail-able evidence suggest a cause-and-effect relationship be-tween the ingestion of erectile dysfunction drugs and thedevelopment of NAION’’. These authors proved that noctur-nal arterial hypotension is the precipitating risk factor forNAION and Viagra can increase this nocturnal hypotension.Additionally Hayreh3 showed that Viagra can be associatedwith an increase of norepinephrine levels that can producevasoconstriction and ischemia in the optic nerve head.Hayreh3 concluded that the chances of NAION after taking

Figure 2. Visual campimetry OU in 10 patients, presented after episodes of non-arteritic, anterior, ischemic optic neuropathy. A. OD. B. OS.

Sequential, NAION in patients taking sildenafil 245

Viagra intake depend on the number of predisposing risk fac-tors for the development of NAION and how much nocturnalhypotension develops after Viagra intake.

In our case series 9 of 10 patients were diabetic and someof them had other cardiovascular risk factors (hypertension,hyperlipidemia and coronary stent). In view of the presenceof these risk factors we conclude that our patients were ata much greater risk of developing NAION following the useof Sildenafil compared to normal healthy individuals.11

Evaluation of the literature on this topic indicates thatthere is no contraindication of PDE-5 use in patients with apast history of monocular NAION.1,4,5,9,12–15 However, thereis a statement by the FDA and a Statement of European Sup-plementary protection certificate class labeling.1,4,5,9,12–15

Fraunfelder et al.,15 reported episodes of NAION after asingle dose (at a single point in time) and after multipledoses. Our series presents a group of patients who sufferedfrom consecutive episodes of NAION. All of these patientsreported the continued use (multiple doses >3–4 times permonth) of Sildenafil before and after the first episode ofNAION. All of these patients also continued to use Sildenafilafter the first episode of NAION until the development ofNAION in the contralateral eye.

There are some limitations in this study. For example, theincomplete data on the exact dose of Sildenafil taken and thetime interval between intake and the development of visualsymptoms. However these data are difficult to collect dueto the limited importance given to medicine by individuals

246 A. Galvez-Ruiz, N. Arishi

in the region of the country where this study was performed.Additionally medical resources are also scarce as this a re-mote region. However, routine exposure to Sildenafil (>2–3times per week) was confirmed in all of the patients duringthe weeks and months prior to the ocular ischemia. (seeFig. 2)

Half of the patients in the current study had a primary epi-sode of unilateral ischemic optic neuropathy; after this epi-sode, they did not seek care from an ophthalmologist orthe episode was somehow unnoticed or subclinical to the pa-tients. For three of these patients, after the first episode ofischemic optic neuropathy, the ophthalmologist in chargeof emergencies did inquire about Sildenafil intake. Due tothis oversight, discontinuation of Sildenafil was not recom-mended. These three patients suffered from a second epi-sode of ischemic optic neuropathy, at which time they werequeried about Sildenafil intake.

Of note, we found spontaneous reporting by the patientthat the use of PDE-5 continues to be a source of embarrass-ment, especially if his wife or son/daughter are present dur-ing the consult. This observation has been reportedpreviously.13,16 This fact indicates that ophthalmologistsassessing a patient after an episode of unilateral ischemic op-tic neuropathy must inquire about the use of PDE-5.

We believe that this is the largest series published to dateand the observations reinforce the general consensus for thecontraindication of PDE-5 in patients with a history of unilat-eral NAION.

Conflict of interest

The authors declared that there is no conflict of interest.

Financial Disclosure

The authors have no relevant financial interests to report.

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